EP1253922A2 - Stimulateurs de croissance osseuse de type statine - Google Patents

Stimulateurs de croissance osseuse de type statine

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Publication number
EP1253922A2
EP1253922A2 EP01903155A EP01903155A EP1253922A2 EP 1253922 A2 EP1253922 A2 EP 1253922A2 EP 01903155 A EP01903155 A EP 01903155A EP 01903155 A EP01903155 A EP 01903155A EP 1253922 A2 EP1253922 A2 EP 1253922A2
Authority
EP
European Patent Office
Prior art keywords
bone
compounds
alkyl
compound
post
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01903155A
Other languages
German (de)
English (en)
Inventor
Gregory R. Mundy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
OsteoScreen Inc
Original Assignee
OsteoScreen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by OsteoScreen Inc filed Critical OsteoScreen Inc
Publication of EP1253922A2 publication Critical patent/EP1253922A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH

Definitions

  • the invention relates to treatment of bone disorders in vertebrates including fractures and cartilage disorders.
  • the invention concerns methods to treat these conditions, and in particular to effect stimulation of osteoblasts and bone formation by use of a preferred group of statin-type compounds.
  • Bone is subject to constant breakdown and resynthesis in a complex process mediated by osteoblasts, which produce new bone, and osteoclasts, which destroy bone.
  • the activities of these cells are regulated by a large number of cytokines and growth factors, many of which have now been identified and cloned.
  • osteoporosis there is a plethora of conditions which are characterized by the need to enhance bone formation. Perhaps the most obvious is the case of bone fractures, where it would be desirable to stimulate bone growth and to hasten and complete bone repair. Agents that enhance bone formation would also be useful in facial reconstruction procedures. Other bone deficit conditions include bone segmental defects, periodontal disease, metastatic bone disease, osteolytic bone disease and conditions where connective tissue repair would be beneficial, such as healing or regeneration of cartilage defects or injury. Also of great significance is the chronic condition of osteoporosis, including age-related osteoporosis and osteoporosis associated with post-menopausal hormone status.
  • statins in general including, for example, mevastatin, lovastatin, simvastatin, and other known statin-type molecules have been shown to enhance directly the production of bone by stimulating osteoblast proliferation and/or differentiation, as described in PCT publication WO 98/25460 published 18 June 1998 and incorporated herein by reference. This published application further describes the use of these members of the statin family in treatment of bone related disorders. It has now been found that a specific subset of statin-type molecules is particularly useful in treatment of bone conditions, and in particular in enhancing bone formation by stimulating osteoblasts. The present application is directed to methods to treat bone disorders using this subset of the statin class.
  • the invention provides statin-type compounds that can be administered as ordinary pharmaceuticals and in particular have the metabolic effect of directly enhancing bone growth. These statins can be confirmed in this property using appropriate assays as described below.
  • the invention is directed to methods and compositions for stimulating the growth of skeletal (bone) tissue, which methods and compositions use, as at least one of the active ingredients, compounds of the formula:
  • R' is H, a cation, or alkyl (1-6C);
  • Z is N or C, and the symbol
  • the compounds of the invention may also be in the form of their corresponding lactones. Particularly preferred in this group are the known statins cerivastatin, atorvastatin, and NK- 104.
  • Figure 1 shows the structures of cerivastatin, atorvastatin and NK-104.
  • the ultimate goal of the methods and compositions of the invention is to treat or ameliorate bone disorders in vertebrate subjects, particularly mammals, and more particularly humans.
  • treat or “treatment” include a postponement of development of bone deficit symptoms and/or a reduction in the severity of such symptoms that will or are expected to develop.
  • the terms further include ameliorating existing bone or cartilage deficit symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, preventing or reversing bone resorption and/or encouraging bone growth.
  • the terms denote that a beneficial result has been conferred on a vertebrate subject with a cartilage, bone or skeletal deficit, or with the potential to develop such deficit.
  • bone deficit is meant an imbalance in the ratio of bone formation to bone resorption, such that, if unmodified, the subject will exhibit less bone than desirable, or the subject's bones will be less intact and coherent than desired. Bone deficit may also result from fracture, from surgical intervention or from dental or periodontal disease.
  • cartilage defect is meant damaged cartilage, less cartilage than desired, or cartilage that is less intact and coherent than desired.
  • Body disorders includes both bone deficits and cartilage defects.
  • Representative uses of the compounds of the present invention include: repair of bone defects and deficiencies, such as those occurring in closed, open and non-union fractures; prophylactic use in closed and open fracture reduction; promotion of bone healing in plastic surgery; stimulation of bone ingrowth into non-cemented prosthetic joints and dental implants; elevation of peak bone mass in pre-menopausal women; treatment of growth deficiencies; treatment of periodontal disease and defects, and other tooth repair processes; increase in bone formation during distraction osteogenesis; and treatment of other skeletal disorders, such as age-related osteoporosis, post-menopausal osteoporosis, glucocorticoid-induced osteoporosis or disuse osteoporosis and arthritis, or any condition that benefits from stimulation of bone formation.
  • bone defects and deficiencies such as those occurring in closed, open and non-union fractures
  • prophylactic use in closed and open fracture reduction promotion of bone healing in plastic surgery
  • stimulation of bone ingrowth into non-cemented prosthetic joints and dental implants elevation of peak bone mass in pre-menopausal women
  • the compounds of the present invention can also be useful in repair of congenital, trauma-induced or surgical resection of bone (for instance, for cancer treatment), and in cosmetic surgery. Further, the compounds of the present invention can be used for limiting or treating cartilage defects or disorders, and may be useful in wound healing or tissue repair.
  • compositions useful in the invention may be administered systemically or locally.
  • the compounds herein are formulated for parenteral (e.g. , intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal or transdermal) or enteral (e.g., oral or rectal) delivery according to conventional methods.
  • Intravenous administration can be by a series of injections or by continuous infusion over an extended period. Administration by injection or other routes of discretely spaced administration can be performed at intervals ranging from weekly to once to three times daily.
  • the compounds disclosed herein may be administered in a cyclical manner (administration of disclosed compound; followed by no administration; followed by administration of disclosed compound, and the like).
  • pharmaceutical formulations will include a compound of the present invention in combination with a pharmaceutically acceptable vehicle, such as saline, buffered saline, 5% dextrose in water, borate-buffered saline containing trace metals or the like.
  • a pharmaceutically acceptable vehicle such as saline, buffered saline, 5% dextrose in water, borate-buffered saline containing trace metals or the like.
  • Formulations may further include one or more excipients, preservatives, solubilizers, buffering agents, albumin to prevent protein loss on vial surfaces, lubricants, fillers, stabilizers, etc.
  • Methods of formulation are well known in the art and are disclosed, for example, in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton PA, which is incorporated herein by reference.
  • compositions for use within the present invention can be in the form of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art.
  • Local administration may be by injection at the site of injury or defect, or by insertion or attachment of a solid carrier at the site, or by direct, topical application of a viscous liquid, or the like.
  • the delivery vehicle preferably provides a matrix for the growing bone or cartilage, and more preferably is a vehicle that can be absorbed by the subject without adverse effects.
  • compositions such as those described in PCT application WO 93/20859, which is incorporated herein by reference.
  • Films of this type are particularly useful as coatings for prosthetic devices and surgical implants.
  • the films may, for example, be wrapped around the outer surfaces of surgical screws, rods, pins, plates and the like.
  • Implantable devices of this type are routinely used in orthopedic surgery.
  • the films can also be used to coat bone filling materials, such as hydroxyapatite blocks, demineralized bone matrix plugs, collagen matrices and the like.
  • a film or device as described herein is applied to the bone at the fracture site. Application is generally by implantation into the bone or attachment to the surface using standard surgical procedures.
  • the biodegradable films and matrices may include other active or inert components.
  • agents that promote tissue growth or infiltration such as growth factors.
  • growth factors include epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factors (TGFs), parathyroid hormone (PTH), leukemia inhibitory factor (LIF), insulin-like growth factors (IGFs) and the like.
  • agents that promote bone growth such as bone morphogenetic proteins (U.S. Patent No. 4,761,471; PCT Publication WO 90/11366), osteogenin (Sampath, et al, Proc. Natl Acad.
  • Biodegradable films or matrices include calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, polyanhydrides, bone or dermal collagen, pure proteins, extracellular matrix components and the like and combinations thereof. Such biodegradable materials may be used in combination with non-biodegradable materials, to provide desired mechanical, cosmetic or tissue or matrix interface properties.
  • Alternative methods for delivery of compounds of the present invention include use of ALZET osmotic minipumps (Alza Corp., Palo Alto, CA); sustained release matrix materials such as those disclosed in Wang, et al. (PCT Publication WO 90/11366); electrically charged dextran beads, as disclosed in Bao, et al, (PCT Publication WO 92/03125); collagen-based delivery systems, for example, as disclosed in Ksander, et al, Ann. Surg. (1990) 211(3):288-94; methylcellulose gel systems, as disclosed in Beck, et al, J. Bone Min. Res.
  • the vertebrate can be administered an anti-resorptive compound to maintain the corrected bone condition.
  • the compounds disclosed herein may be administered with an anti-resorptive compound in a cyclical manner (administration of disclosed compound, followed by anti-resorptive, followed by disclosed compound, and the like).
  • conventional preparations such as those described below may be used.
  • Aqueous suspensions may contain the active ingredient in admixture with pharmacologically acceptable excipients, comprising suspending agents, such as methyl cellulose; and wetting agents, such as lecithin, lysolecithin or long-chain fatty alcohols.
  • the said aqueous suspensions may also contain preservatives, coloring agents, flavoring agents, sweetening agents and the like in accordance with industry standards.
  • Preparations for topical and local application comprise aerosol sprays, lotions, gels and ointments in pharmaceutically appropriate vehicles which may comprise lower aliphatic alcohols, polyglycols such as glycerol, polyethylene glycol, esters of fatty acids, oils and fats, and silicones.
  • the preparations may further comprise antioxidants, such as ascorbic acid or tocopherol, and preservatives, such as p-hydroxybenzoic acid esters.
  • Parenteral preparations comprise particularly sterile or sterilized products.
  • Injectable compositions may be provided containing the active compound and any of the well known injectable carriers. These may contain salts for regulating the osmotic pressure.
  • the osteogenic agents can be incorporated into liposomes by any of the reported methods of preparing liposomes for use in treating various pathogenic conditions.
  • the present compositions may utilize the compounds noted above incorporated in liposomes in order to direct these compounds to macrophages, monocytes, as well as other cells and tissues and organs which take up the liposomal composition.
  • the liposome-incorporated compounds of the invention can be utilized by parenteral administration, to allow for the efficacious use of lower doses of the compounds.
  • Ligands may also be incorporated to further focus the specificity of the liposomes.
  • Suitable conventional methods of liposome preparation include, but are not limited to, those disclosed by Bangham, A.D., et al, JMolBiol (1965) 23:238-252, Olson, F., et al, Biochim Biophys Acta (1979) 557:9-23, Szoka, F., et al, Proc Natl Acad Sci USA (1978) 75:4194-4198, Kim, S., et al, Biochim Biophys Acta (1983) 728:339:348, and Mayer, et al, Biochim Biophys Acta (1986) 858:161-168.
  • the liposomes may be made from the present compounds in combination with any of the conventional synthetic or natural phospholipid liposome materials including phospholipids from natural sources such as egg, plant or animal sources such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingomyelin, phosphatidylserine, or phosphatidylinositol and the like.
  • natural sources such as egg, plant or animal sources such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingomyelin, phosphatidylserine, or phosphatidylinositol and the like.
  • Synthetic phospholipids that may also be used, include, but are not limited to: dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidycholine, and the corresponding synthetic phosphatidylethanolamines and phosphatidylglycerols.
  • Cholesterol or other sterols, cholesterol hemisuccinate, glycolipids, cerebrosides, fatty acids, gangliosides, sphingolipids, l,2-bis(oleoyloxy)-3-(trimethyl ammonio) propane (DOTAP), N-[l-(2,3-dioleoyl) propyl-N,N,N-trimethylammonium chloride (DOTMA), and other cationic lipids may be incorporated into the liposomes, as is known to those skilled in the art.
  • the relative amounts of phospholipid and additives used in the liposomes may be varied if desired.
  • the preferred ranges are from about 60 to 90 mole percent of the phospholipid; cholesterol, cholesterol hemisuccinate, fatty acids or cationic lipids may be used in amounts ranging from 0 to 50 mole percent.
  • the amounts of the present compounds incorporated into the lipid layer of liposomes can be varied with the concentration of the lipids ranging from about 0.01 to about 50 mole percent.
  • the liposomes with the above formulations may be made still more specific for their intended targets with the incorporation of monoclonal antibodies or other ligands specific for a target.
  • monoclonal antibodies to the BMP receptor may be incorporated into the liposome by linkage to phosphatidylethanolamine (PE) incorporated into the liposome by the method of Leserman, L., et al, Nature (1980) 288:602-604.
  • PE phosphatidylethanolamine
  • Veterinary uses of the disclosed compounds are also contemplated. Such uses would include treatment of bone or cartilage deficits or defects, i.e., bone disorders, in domestic animals, livestock and thoroughbred horses.
  • the compounds of the present invention may be used to stimulate growth of bone-forming cells or their precursors, or to induce differentiation of bone-forming cell precursors, either in vitro or ex vivo.
  • the compounds described herein may also modify a target tissue or organ environment, so as to attract bone-forming cells to an environment in need of such cells.
  • precursor cell refers to a cell that is committed to a differentiation pathway, but that generally does not express markers or function as a mature, fully differentiated cell.
  • the term "mesenchymal cells” or “mesenchymal stem cells” refers to pluripotent progenitor cells that are capable of dividing many times, and whose progeny will give rise to skeletal tissues, including cartilage, bone, tendon, ligament, marrow stroma and connective tissue (see A. Caplan, J. Orthop. Res. (1991) 9:641-50).
  • the term "osteogenic cells” includes osteoblasts and osteoblast precursor cells. More particularly, the disclosed compounds are useful for stimulating a cell population containing marrow mesenchymal cells, thereby increasing the number of osteogenic cells in that cell population.
  • osteogenic cells are removed from the cell population, either before or after stimulation with the disclosed compounds.
  • osteogenic cells may be expanded.
  • the expanded osteogenic cells can be infused (or reinfused) into a vertebrate subject in need thereof.
  • a subject's own mesenchymal stem cells can be exposed to compounds of the present invention ex vivo, and the resultant osteogenic cells could be infused or directed to a desired site within the subject, where further proliferation and or differentiation of the osteogenic cells can occur without immunorejection.
  • the cell population exposed to the disclosed compounds may be immortalized human fetal osteoblastic or osteogenic cells.
  • an "effective amount" of a composition is that amount which produces a statistically significant effect.
  • an "effective amount" for therapeutic uses is the amount of the composition comprising an active compound herein required to provide a clinically significant increase in healing rates in fracture repair; reversal of bone loss in osteoporosis; reversal of cartilage defects or disorders; prevention or delay of onset of osteoporosis; stimulation and/or augmentation of bone formation in fracture non-unions and distraction osteogenesis; increase and/or acceleration of bone growth into prosthetic devices; and repair of dental defects.
  • Such effective amounts will be determined using routine optimization techniques and are dependent on the particular condition to be treated, the condition of the patient, the route of administration, the formulation, and the judgment of the practitioner and other factors evident to those skilled in the art.
  • the dosage required for the compounds of the invention is manifested as a statistically significant difference in bone mass between treatment and control groups.
  • This difference in bone mass may be seen, for example, as a 5-20% or more increase in bone mass in the treatment group.
  • Other measurements of clinically significant increases in healing may include, for example, tests for breaking strength and tension, breaking strength and torsion, 4-point bending, increased connectivity in bone biopsies and other biomechanical tests well known to those skilled in the art.
  • General guidance for treatment regimens is obtained from experiments carried out in animal models of the disease of interest.
  • the dosage of the compounds of the invention will vary according to the extent and severity of the need for treatment, the activity of the administered compound, the general health of the subject, and other considerations well known to the skilled artisan. Generally, they can be administered to a typical human on a daily basis as an oral dose of about 0.1 mg/kg- 1000 mg/kg, and more preferably from about 1 mg/kg to about 200 mg/kg. The parenteral dose will appropriately be 20-100% of the oral dose. While oral administration may be preferable in most instances (for reasons of ease, patient acceptability, and the like), alternative methods of administration may be appropriate for selected compounds and selected defects or diseases. In comparative assays, positive control compounds or other bone-active test compounds may be administered subcutaneously, while statin-type test compounds are administered orally.
  • the osteogenic activity of the compounds of formula 1 used in the methods of the invention can be verified in various assay systems.
  • Neonatal Mouse Calvaria Assay (In vitro )
  • the medium used when the assay is conducted to assess bone formation is Fitton and Jackson Modified BGJ Medium (Sigma) supplemented with 6 ⁇ g/ml insulin, 6 ⁇ g/ml transferrin, 6 ng/ml selenous acid, calcium and phosphate concentrations of 1.25 and 3.0 mM, respectively, and ascorbic acid to a concentration of 100 ⁇ g/ml is added every two days.
  • the incubation is conducted at 37°C in a humidified atmosphere of 5% CO 2 and 95% air for 96 hours. Following this, the bones are removed from the incubation media and fixed in 10% buffered formalin for 24-48 hours, decalcified in 14% EDTA for 1 week, processed through graded alcohols; and embedded in paraffin wax.
  • Three ⁇ m sections of the calvaria are prepared. Representative sections are selected for histomorphometric assessment of bone formation or bone resorption. Bone changes are measured on sections cut 200 ⁇ m apart. Osteoblasts and osteoclasts are identified by their distinctive morphology.
  • auxiliary assays can be used as controls to determine non-BMP promoter-mediated effects of test compounds.
  • mitogenic activity can be measured using screening assays featuring a serum-response element (SRE) as a promoter and a luciferase reporter gene. More specifically, these screening assays can detect signaling through SRE-mediated pathways, such as the protein kinase C pathway. For instance, an osteoblast activator SRE-luciferase screen and an insulin mimetic SRE-luciferase screen are useful for this purpose.
  • test compound stimulation of cAMP response element (CRE)-mediated pathways can also be assayed.
  • CRE cAMP response element
  • cells transfected with receptors for PTH and calcitonin can be used in CRE-luciferase screens to detect elevated cAMP levels.
  • the BMP promoter specificity of a test compound can be examined through use of these types of auxiliary assays.
  • mice Male ICR Swiss white mice, aged 4-6 weeks and weighing 13-26 gm, are employed, using 4-5 mice per group.
  • the calvarial bone growth assay is performed as described in PCT application WO 95/24211, incorporated by reference. Briefly, the test compound or appropriate control vehicle is injected into the subcutaneous tissue over the right calvaria of normal mice.
  • the control vehicle is the vehicle in which the compound was solubilized, and is PBS containing 5% DMSO or is PBS containing Tween (2 ⁇ l/10 ml). The animals are sacrificed on day 14 and bone growth measured by histomorphometry.
  • Bone samples for quantitation are cleaned from adjacent tissues and fixed in 10% buffered formalin for 24-48 hours, decalcified in 14% EDTA for 1-3 weeks, processed through graded alcohols; and embedded in paraffin wax.
  • Three to five ⁇ m sections of the calvaria are prepared, and representative sections are selected for histomorphometric assessment of the effects on bone formation and bone resorption. Sections are measured by using a camera lucida attachment to trace directly the microscopic image onto a digitizing plate. Bone changes are measured on sections cut 200 ⁇ m apart, over 4 adjacent lxl mm fields on both the injected and noninjected sides of the calvaria. New bone is identified by its characteristic woven structure, and osteoclasts and osteoblasts are identified by their distinctive morphology. Histomorphometry software (OsteoMeasure, Osteometrix, Inc., Atlanta) is used to process digitizer input to determine cell counts and measure areas or perimeters.
  • Prototypical dosing may be accomplished by subcutaneous, intraperitoneal or oral administration, and may be performed by injection, sustained release or other delivery techniques.
  • the time period for administration of test compound may vary (for instance, 28 days as well as 35 days may be appropriate).
  • An exemplary, in vivo oral or subcutaneous dosing assay may be conducted as follows:
  • 70 three-month-old female Sprague-Dawley rats are weight-matched and divided into seven groups, with ten animals in each group. This includes a baseline control group of animals sacrificed at the initiation of the study; a control group administered vehicle only; a PBS-treated control group; and a positive control group administered a compound (non-protein or protein) known to promote bone growth. Three dosage levels of the compound to be tested are administered to the remaining three groups.
  • test compound positive control compound, PBS, or vehicle alone is administered subcutaneously once per day for 35 days. All animals are injected with calcein nine days and two days before sacrifice (two injections of calcein administered each designated day). Weekly body weights are determined. At the end of the 35-day cycle, the animals are weighed and bled by orbital or cardiac puncture. Serum calcium, phosphate, osteocalcin, and CBCs are determined.
  • Such assays may also include an estrogen-treated group as a control.
  • An exemplary subcutaneous dosing assay is performed as follows:
  • a typical study 80 three-month-old female Sprague-Dawley rats are weight-matched and divided into eight groups, with ten animals in each group. This includes a baseline control group of animals sacrificed at the initiation of the study; three control groups (sham ovariectomized (sham ONX) + vehicle only; ovariectomized (ONX) + vehicle only; PBS-treated ONX); and a control ONX group that is administered a compound known to promote bone growth. Three dosage levels of the compound to be tested are administered to the remaining three groups of ONX animals.
  • test compound positive control compound, PBS, or vehicle alone is administered orally or subcutaneously once per day for 35 days.
  • test compound can be formulated in implantable pellets that are implanted for 35 days, or may be administered orally, such as by gastric gavage. All animals, including sham ONX/vehicle and ONX vehicle groups, are injected intraperitoneally with calcein nine days and two days before sacrifice (two injections of calcein administered each designated day, to ensure proper labeling of newly formed bone). Weekly body weights are determined. At the end of the 35-day cycle, the animals' blood and tissues are processed as described above.
  • Compounds may also be tested in chronic ONX animals (treatment model).
  • An exemplary protocol for treatment of established bone loss in ovariectomized animals that can be used to assess efficacy of anabolic agents may be performed as follows. Briefly, 80 to 100 six month old female, Sprague-Dawley rats are subjected to sham surgery (sham ONX) or ovariectomy (ONX) at time 0, and 10 rats are sacrificed to serve as baseline controls. Body weights are recorded weekly during the experiment. After approximately 6 weeks (42 days) or more of bone depletion, 10 sham ONX and 10 ONX rats are randomly selected for sacrifice as depletion period controls. Of the remaining animals, 10 sham ONX and 10 ONX rats are used as placebo-treated controls.
  • the remaining ONX animals are treated with 3 to 5 doses of test drug for a period of 5 weeks (35 days).
  • a group of ONX rats can be treated with an agent such as PTH, a known anabolic agent in this model (Kimmel, et al, Endocrinology (1993) 132:1577-84).
  • PTH a known anabolic agent in this model
  • the proximal left and right tibiae are used for pQCT measurements, cancellous bone mineral density (BMD) (gravimetric determination), and histology, while the midshaft of each tibiae is subjected to cortical BMD or histology.
  • BMD cancellous bone mineral density
  • the femurs are prepared for pQCT scanning of the midshaft prior to biomechanical testing.
  • LN2 are processed for BMD (pQCT may also be performed);
  • LN3 are prepared for undecalcified bone histology; and LN4 are processed for mechanical testing.
  • the compounds of the invention may be in the open chain form, as shown, or may be in the form of a lactone.
  • the compounds contain chiral carbons; all stereoisomeric forms of these compounds and mixtures thereof are included.
  • the statin compounds useful in the methods of the invention contain an aromatic or heteroaromatic system represented by:
  • aromatic or heteroaromatic system is meant a monocyclic or fused bicyclic system which is aromatic in nature and which contains 5-12 ring members. Typical aromatic systems are, of course, benzene and naphthalene.
  • the carbon in one or more positions may be replaced by nitrogen, sulfur, or oxygen. Replacement by nitrogen is preferred.
  • the heteroaromatic system may preferably be pyrrole, pyrazole, imidazole, pyridine, pyrazine, pyrimidine, indole, purine, benzimidazole, quinoline, isoquinoline, quinazoline, and the like. Particularly preferred are pyrrole, quinoline, and pyridine.
  • Z occupies position 1 ; when the heteroaromatic system is quinoline, it is preferred that Z is at position 3, and when the heteroaromatic system is pyridine, position 3 for Z is also preferred.
  • the heteroaromatic system is required to be substituted at the position adjacent Z by p-fluorophenyl.
  • Additional substituents may also be present. These substituents may contain additional aromatic groups, and may be alkyl, including cycloalkyl, OR, SR, NR 2 , and the like wherein R is H or alkyl (1-6C), halo, and or phenyl. Substituents also may include those of the formula R"COO, R"CONH,
  • the compounds of the invention which are useful in treating bone disorders by enhancing bone growth are generally classified as "statins.” Particularly preferred for use in the invention are cerivastatin, marketed under the name Baycol ® by Bayer (See
  • compositions of the invention may also include the bisphosphonates and their analogs. Typically, and preferably, the bisphosphonates are of the formula
  • Typical salts are those of the inorganic ions, such as sodium ion, potassium ion, calcium ion, magnesium ion and the like; any pharmaceutically acceptable cation may be used.
  • Typical esters are the ethyl, methyl, isobutyl, ethylene glycol, and other typical pharmaceutically acceptable esters; typical amides are the unsubstituted -NH 2 amides as well as the alkyl and dialkyl amides.
  • Embodiments of R 10 include halo, OR, SR, NR 2 , where R is H or alkyl (1-6C) or alkyl or arylalkyl with optional substitutions. Particularly preferred are the amino-substituted alkyl embodiments.
  • both R 10 are not identical, although in some embodiments, such as clodronate, both R 10 are halo.
  • Particularly preferred compounds among the bisphosphonates are risedronate, alandronate, pamidronate, clodronate and in particular ibandronate. These compounds are particularly useful in combination with the statins.
  • compositions may also include other agents, including those which inhibit bond resorption such as estrogens or their analogs and compounds of the formula Ar-L-Ar wherein Ar represents an aryl substituent and L represents a linker.
  • Cerivastatin, atorvastatin and NK-104 are assayed in vivo according to the procedure described previously (see “In vivo Assay of Effects of Compounds on Murine Calvarial Bone Growth,” supra). Vehicle control, bFGF and varying doses of test compound are tested.
  • Cerivastatin, atorvastatin and NK-104 and appropriate controls are assayed in vitro (ex vivo) for bone formation activity (described above in "Neonatal Mouse Calvaria Assay (in vitro)"). Histomorphometrical assessments of e vivo calvaria are carried out using an OsteoMetrics bone morphometry measurement program, according to the manufacturer's instructions. Measurements are determined using either a 10- or 20-fold objective with a standard point counting eyepiece graticule.
  • New bone formation is determined (using a 10X objective) by measuring the new bone area formed in one field in 3 representative sections of each bone (4 bones per group). Each measurement is carried out J field distance from the end of the suture. Both total bone and old bone area were measured. Data are expressed as new bone area in mm 2 .
  • Osteoblast numbers are determined by point counting. The number of osteoblast cells lining the bone surface on both sides of the bone are counted in one field using a 20X objective. Data are expressed as osteoblast numbers/mm of bone surface.
  • Cerivastatin, atorvastatin and NK-104 and controls are tested in an antiresorptive assay. Briefly, 15 day timed pregnant CD-I female mice are injected with 45 Ca (25 ⁇ Ci/mouse). The calvaria from the 4 day old pups are dissected out and cut in half. The excised half calvaria are placed on metal grids (at the surface) in 1 ml of BGJ medium (Sigma) containing 0.1% BSA with glutamine and Pen/Strep added. The bones are incubated at 37°C in a 5% humidified incubator for a period of 24 h, and then transferred to wells containing 1 ml medium with factors added (IL-1, PTH, and/or test compounds).
  • the treated bones are incubated under the above conditions for a further 72 h. After this incubation period, the bones are removed and placed into 20% TCA in a scintillation vial for 1.5 h, and then counted with scintillation fluid. An aliquot of medium (0.4 ml) is also counted. The results are expressed as % 45 Ca release.
  • This assay may be modified by including test compounds/factors or control compounds/factors in the preincubation medium (i.e., during the first 24 h). Since most of the osteoclasts are formed in the calvaria following the preincubation period, compounds or factors that affect osteoclast formation may have a greater effect during the preincubation period.
  • Cerivastatin, atorvastatin and NK-104 are also analyzed in vivo using an acute OVX (prevention model) and/or chronic (treatment model) OVX model system, as described above under "Additional In Vivo Assays".
  • Cerivastatin, atorvastatin and NK-104 are examined for effects on surgical defects in the rabbit radius. Healing of these defects may be assessed by X-ray, histology and biomechanical strength.
  • test compound is weighed out in a microcentrifuge tube, and 50 ⁇ l of 1.5% sodium alginate solution is added as a carrier. This test sample is vortexed to wet all of the powder. The sample is sonicated for 20-30 min, and then vortexed again. Disks are created in the top of the microcentrifuge tube (by placing the tube lid or stopper-side down). The indent in the top of the stopper (i.e., lid) is used to form the disk (7.5 mm diameter). CaCl solution (100 ⁇ l of 100 mM) is added to the sodium alginate/drug solution. The samples are allowed to sit for 5-10 min, and then the calcium-alginate disks are carefully removed.
  • the disks are rinsed in a beaker filled with water to rinse off the excess calcium solution, and are saved in tubes using water as vehicle. All solutions and containers are sterile, and all procedures for preparations of disks are performed under a laminar flow hood under sterile conditions.

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Abstract

La présente invention concerne des composés de la formule (1), et les formes lactones de ces derniers, dans laquelle R' est H, un cation, ou un alkyle en C1-6 ; Y est -CH2CH2- ou -CH=CH-; Z est N ou C, et le symbole (a) représente un système cyclique aromatique ou hétéroaromatique qui peut facultativement être encore substitué, outre le substituant p-fluorophényle indiqué, afin de stimuler la formation osseuse, et qui sont par conséquent utilisés dans le traitement de l'ostéoporose, des fractures ou des déficiences osseuses, de l'hyperparathyroïdisme primaire ou secondaire, des parodontopathies ou défauts parodontaux, des maladies osseuses métastatiques, des maladies osseuses ostéolytiques, et dans les traitements suivant les opérations plastiques, les opérations prothétiques des articulations et les implantations dentaires.
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